Summary

Umeclidinium bromide is a new long‑acting muscarinic antagonist (LAMA) for chronic obstructive pulmonary disease (COPD). Studies have shown improvements in forced expired volume in 1 second (FEV1) compared with placebo. Patient‑orientated outcomes such as dyspnoea have had varying results with some showing an improvement and others showing no difference compared with placebo. There are no published studies which directly compare the licensed dose with a currently available LAMA or long‑acting beta2 agonist (LABA).

Regulatory status: Umeclidinium (Incruse) received a European marketing authorisation in April 2014 and was launched in the UK in October 2014.

The SPC states that cardiovascular effects, such as cardiac arrhythmias, atrial fibrillation and tachycardia, may be seen after the administration of muscarinic receptor antagonists, including umeclidinium.

The SPC states that umeclidinium should be used with caution in people with severe cardiovascular disease, particularly cardiac arrhythmias. In addition, it states that consistent with its antimuscarinic activity, umeclidinium should be used with caution in people with urinary retention or with narrow‑angle glaucoma.

Patient factors

Once daily dosage. Other LAMAs such as tiotropium and glycopyrronium are also used once a day.

The cost of 30 days' supply of an alternative currently available LAMA ranges from approximately £27.50 to £34.87.

Umeclidinium offers a modest cost saving over tiotropium but not over newer LAMAs such as glycopyrronium or aclidinium.

Introduction and current guidance

The NICE guideline on chronic obstructive pulmonary disease (COPD) states that COPD is characterised by airflow obstruction that is usually progressive and not fully reversible; it is predominantly caused by smoking. The guideline makes several recommendations about inhaled treatments for managing stable COPD, which are relevant to the likely place in therapy of umeclidinium (Incruse, a LAMA inhaler). See the NICE guideline or the NICE pathway on COPD for full details.

Product overview

Incruse is a multi‑dose, dry powder inhaler containing umeclidinium bromide (a LAMA). The recommended dose is 1 inhalation once a day. Each delivered dose (the dose that leaves the mouthpiece of the inhaler) contains 55 micrograms umeclidinium which is equivalent to 65 micrograms of umeclidinium bromide. This corresponds to a pre‑dispensed dose of 62.5 micrograms umeclidinium equivalent to 74.2 micrograms umeclidinium bromide (Incruse summary of product characteristics).Throughout this evidence summary the licensed umeclidinium dose is referred to as umeclidinium 55 micrograms.

Evidence review

This evidence summary is based on the best available published evidence. This is 2 randomised controlled trials (RCTs): Trivedi et al. 2014 and Donohue et al. 2013. Both studies had trough FEV1 as primary outcomes.

Trivedi et al. 2014 found that there was a statistically significant improvement in trough FEV1 of 0.127 litres (95% confidence interval [CI] 0.052 to 0.202; p<0.001) with umeclidinium 55 micrograms compared with placebo after 12 weeks' treatment. Donohue et al. 2013 found a statistically significant improvement in trough FEV1 of 0.115 litres (95% CI 0.076 to 0.155; p≤0.001) with umeclidinium 55 micrograms compared with placebo after 24 weeks' treatment. The full NICE guideline on COPD considers 0.100 litres to be the minimum clinically important difference for change in FEV1.

Trivedi et al. 2014 and Donohue et al. 2013 both included patient‑orientated secondary and additional outcomes. Donohue et al. 2013 reported a statistically significant improvement in the transition dyspnoea index (TDI) score with umeclidinium 55 micrograms compared with placebo (1.0 unit; 95% CI 0.5 to 1.5; p≤0.001) at 24 weeks. The full NICE guideline considers 1.0 unit to be the minimum clinically important difference for TDI score. However, in the study by Trivedi et al. 2014 there was no statistically significant difference between umeclidinium 55 micrograms and placebo for this outcome at 12 weeks.

Trivedi et al. 2014 found a statistically significant improvement in the St George's Respiratory Questionnaire (SGRQ) score of −7.90 points (95% CI −12.20 to −3.60; p<0.001) with umeclidinium 55 micrograms compared with placebo; which is greater than the −4 points that the full NICE guideline considers to be the minimum clinically important difference. There was also a statistically significant reduction in rescue salbutamol use with umeclidinium compared with placebo in this study. However, the clinical significance of this reduction (0.7 puffs per day) is unclear. Donohue et al. 2013 found no difference between umeclidinium and placebo for rescue salbutamol use. An improvement in the SGRQ score was seen with umeclidinium compared with placebo in this study; statistical analysis is described for this outcome but it is not strictly inferential due to the statistical testing procedure used in the study.

There are limited long‑term efficacy and safety data for the licensed dose. A long‑term 52‑week safety study (Donohue et al. 2014) has been published. However this study evaluates umeclidinium 113 micrograms and does not include the licensed umeclidinium dose.

Context

Three other single‑component LAMAs are currently licensed for use in COPD in the UK: aclidinium, glycopyrronium and tiotropium. Four single‑component LABAs are currently licensed for use in COPD in the UK: formoterol, indacaterol, olodaterol and salmeterol.

Estimated impact for the NHS

The NICE guideline on COPD recommends that for people with stable COPD and an FEV1 of 50% predicted or more who remain breathless or have exacerbations despite using short‑acting bronchodilators as needed, a LABA or a LAMA should be offered as maintenance therapy. For people with an FEV1 of less than 50% predicted either a LABA with an inhaled corticosteroid (ICS) in a combination inhaler, or a LAMA should be offered. There are only limited data to support the use of umeclidinium alone as ICS were also permitted in the studies. In both Trivedi et al. 2014 and Donohue et al. 2013, ICS at a stable dose of up to 1000 micrograms per day fluticasone propionate or equivalent was allowed throughout the study period; at baseline around 24% of the study population in Trivedi et al. 2014 and around 51% in Donohue et al. 2013 were using ICS.

NICE also recommends that for people who remain breathless or have exacerbations despite taking a LABA with an ICS, a LAMA should be offered in addition to a LABA with an ICS irrespective of the FEV1. Four studies (NCT01772134, NCT01772147, NCT01957163 and NCT02119286) have compared umeclidinium with placebo in a population of people also taking ICS/LABA combination inhalers. However, none of these studies has been published in full. All 4 of these studies had FEV1 primary outcomes.

Both Trivedi et al. 2014 and Donohue et al. 2013 compared umeclidinium with placebo for FEV1 primary outcomes. There are no published studies which directly compare umeclidinium 55 micrograms with a currently available LAMA or LABA.

Umeclidinium is an alternative to the other currently available LAMAs. There are no data to show that it is safer. It offers a modest cost saving over tiotropium but not over newer LAMAs such as glycopyrronium or aclidinium. There are no studies comparing umeclidinium with other available LAMAs, so comparisons cannot be made. It is most likely to make an impact by offering people with COPD another choice of inhaler device.

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.